Chronic Obstructive Pulmonary Disease (COPD) is characterized by a chronic and persistent airflow limitation that is progressive and interferes with normal breathing. It is one of the leading, yet under-recognized causes of morbidity and mortality worldwide. Worldwide, more than 300 million people are estimated to have COPD including an estimated 29 million diagnosed and undiagnosed adults in the US. COPD is the fourth leading cause of death in the U.S. and the third leading cause of death worldwide, something the World Health Organization had not predicted to occur until 2030. The US annual healthcare burden of COPD is estimated at $50 billion per year, and in Europe about EU50 billion In the UK, 115,000 people are diagnosed with COPD each year – that’s a new diagnosis every 5 minutes. Even in people with mild or moderate COPD, work productivity is lower than in people without COPD, and about 3-fold decrease in productivity has been reported in COPD patients with high symptom burden.
COPD is an umbrella term used to describe different pathologies that contribute to patient symptoms of breathlessness, coughing, sputum production, chest tightness and wheezing. Small airway disease refers to obstruction in the smaller airways deep in the lung. Chronic bronchitis may be diagnosed when patients experience significant periods of excess sputum production. Emphysema is the loss of alveolar tissue and lung elasticity, resulting in excess air trapping, or inability to fully exhale, resulting in significant breathlessness. Some forms of asthma in adults may even be included under the umbrella term of COPD.
Airflow obstruction (the blocking of air that normally moves easily into and out of airways in the lungs) occurs when airways become more narrow than normal due to disease. Airway obstruction results from any combination of four basic mechanisms:
- 1. Smooth muscle contraction causes the airways to tighten (bronchoconstriction).
- 2. Excess mucus build-up inside the airways may cause partial or even full obstruction.
- 3. Thickening of the airway walls, caused by inflammation or hypertrophy of the smooth muscle or mucous glands.
- 4. Emphysema (destruction of the lung tissue itself), can lead to a loss of radial traction on the airway walls, leading to airway collapse.
COPD treatment consists of drug therapies to alleviate the patient’s symptoms, stabilize lung function, and reduce the patient’s risk of COPD exacerbation (increased symptoms that require urgent and additional medical treatments). The mainstay of COPD treatment is a class of drugs called “anti-cholinergics”. These drugs prevent the binding of acetylcholine to the M3 receptors on the airway surface. The brain signals the lung to release acetylcholine in response to the lung’s reaction to toxins, such as from tobacco smoke or environmental pollution, generating a repeating cycle of signaling along the nerve pathways between the lung and the brain. Acetylcholine stimulates airway bronchoconstriction and the production of excess mucus, which causes breathing difficulties and worsened symptoms in patients with COPD. Thus anti-cholinergic drugs can alleviate symptoms and improve breathing by preventing uptake of acetylcholine in the lungs of people with COPD.
Rationale for Targeted Lung Denervation
In some COPD patients, however, the constant cycle of nerve signaling and chronic airway inflammation, reflex bronchoconstriction, and bacterial or viral toxins creates a state of heightened neural sensitivity, called airway hyper-responsiveness. This can be thought of as the pulmonary system on “permanent high alert” which results in an over-exaggerated reaction to stimuli such as air pollution, allergens, or second-hand smoke. This causes flooding of acetylcholine release which stimulates airway bronchoconstriction and the production of excess mucus. These patients may therefore suffer from frequent exacerbations which their COPD medications cannot adequately prevent.
The goal of TLD is to disrupt pulmonary nerve input to the lung to reduce the release of acetylcholine. Targeting of acetylcholine is thus mechanistically similar to the therapeutic strategy of anti-cholinergic drugs, except that TLD achieves its benefit in a single bronchoscopic procedure instead of via inhaled medicines that must be taken daily. Denervation of the lung interrupts nerve signaling to and from the lung, which reduces acetylcholine release, allowing airway smooth muscle to relax, and mucous secretion to decrease. The concept is thus to move the pulmonary system from a state of “high alert” (hyper-reactivity) which is associated with increased exacerbations and symptom burden, to a state of “low alert” (diminished hyper-reactivity) to improve symptom tolerance, decrease symptom burden and thereby decrease COPD exacerbations.
For an overview of TLD’s mechanism of action, please click here.
For more information about COPD, the following websites may be useful:
Global Initiative for Chronic Obstructive Lung Disease (GOLD)
European Respiratory Society (ERS)
European Lung Foundation
American Lung Association
National Heart Lung and Blood Institute
To learn more about current COPD treatment options, please consult a healthcare professional.
 Riley, C. and Sciurba, F. Diagnosis and Outpatient Management of COPD: A Review, JAMA 2019
 Kochanek, K.D. Mortality in the United States, 2016. NCHS Data Brief 2017
 European Respiratory Society, European Lung White Book 2013
 https://statistics.blf.org.uk/copd (British Lung Foundation, 2012 data)
 De Sousa Sena, Work productivity loss in mild to moderate COPD: lessons learned from the CanCOLD study, ERJ 2017